A Transcriptomics-Based Computational Drug Repositioning Pipeline Identifies Simvastatin And Primaquine As Novel Therapeutics For Endometriosis Pain

Endometriosis has limited treatment options, prompting the search for novel therapeutics. We previously used a transcriptomics-based computational drug repositioning pipeline to analyze public bulk transcriptomic data of eutopic endometrium from cases and controls and identified several drug candidates. Fenoprofen, our top in silico candidate, was validated in a rat model of endometriosis-associated pain. Building on this, we evaluated herein two additional candidates, simvastatin (a cholesterol-lowering drug) and primaquine (an antimalarial), based on strong endometrial gene expression reversal scores and favorable safety profiles. Using the rat model, we conducted behavioral testing, bulk RNA sequencing, and differential expression analysis to assess their therapeutic potential. We also assessed endometriosis diagnosis among patients prescribed simvastatin in electronic medical records (EMR) across six University of California (UC) healthcare institutions. In vivo validation using a rat model of endometriosis demonstrated that both simvastatin and primaquine significantly reduced vaginal hyperalgesia, a surrogate marker of endometriosis-related pain. RNA-seq of uteri and lesions confirmed reversal of disease-associated gene expression signatures following treatment. Analysis of UC-wide EMR data found lower relative risk of endometriosis among those prescribed simvastatin compared to a matched control group. Overall, simvastatin and primaquine attenuated pain-associated behaviors and reversed endometriosis-related gene expression changes in an animal model. Moreover, simvastatin prescription was associated with a lower relative risk of endometriosis in our retrospective multi-center cohort study. These findings highlight their potential as repurposed therapeutics for endometriosis and support the effectiveness of computational drug repositioning in identifying new treatment strategies. One Sentence SummarySimvastatin and primaquine reduced endometriosis pain and reversed gene signatures, with simvastatin also linked to lower disease risk.